Collecting Duct-specific Deletion of Acid Ceramidase Promoted Sodium Retention and Salt-sensitive Hypertension

Our previous studies have shown that renal medullary sphingosine-1-phosphate (S1P) stimulates urinary sodium excretion via the S1P type 1 receptor (S1PR1), which primarily located in the collecting ducts, and that knockout of S1PR1 in the collecting duct leads to sodium retention and enhanced salt-sensitive hypertension. Preliminary studies using immunostaining showed that acid ceramidase (AC), the upstream rate-limit enzyme for S1P production, was primarily present in collecting ducts in the renal medulla and predominantly in principal cells. The present study tested the hypothesis that the deletion of AC in collecting duct impairs the renal sodium excretion and promotes salt-sensitive hypertension. Mice with collecting duct (CD)-specific knockout of AC (CD-AC-KO) were generated by crossing the AC-encoding gene Asah1-floxed mice with aquaporin 2-Cre mice. Male adult mice were used. High salt intake significantly increased protein levels of AC by 2-fold as well as the S1P levels by 1-fold in the renal medulla in control mice, whereas the high salt-induced increase in S1P levels were substantially inhibited by > 50% in CD-AC-KO mice. Functionally, pressure natriuresis was blunted by 65% and the positive salt balance induced by chronic high salt intake was doubled in CD-AC-KO mice compared with control mice. These results indicated the impairment of renal medullary function and the promotion of sodium retention in CD-AC-KO mice. The treatment of a low dose deoxycorticosterone acetate (DOCA) and high salt intake for 2 weeks produced more significant increase in MAP in CD-AC-KO mice compared with control Mice (136±7mmHg vs 109±4 mmHg). These findings demonstrated that deletion of AC in collecting duct reduced S1P levels, inhibited sodium excretion, promoted sodium retention and accelerated DOCA-salt-induced salt-sensitive hypertension, suggesting that the AC in collecting duct is an important anti-hypertensive pathway by promoting sodium excretion and that impairment of renal medullary AC may represent a novel mechanism for salt-sensitive hypertension. R01DK140219, R01HL145163 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.